Cigarette smoking is the leading preventable cause of death in this country and is an increasing threat to health worldwide. Current pharmacological therapies prescribed for smoking cessation are efficacious. However, the absolute success rates per quit attempt are low (15-35% at one year). The National Institutes of Health recognize the impact that nicotine addiction has on morbidity/mortality, and have made nicotine addiction an NIH trans-institute research priority (NIDA/NCI/NIHLB and NIAAA). This proposal involves the evaluation of a new product that combines bupropion {Zyban?; FDA approved for smoking cessation) and mecamylamine in a once-a-day, controlled-release capsule for oral administration. The clinical advantages anticipated from this unique combination are: 1) increased effectiveness of the combination product over that achievable with bupropion (Zyban?) alone through the addition of a nicotine antagonist (mecamylamine-lnversine?; FDA approved for hypertension); 2) improved safety by reducing the bupropion daily dose from 300 mg to 200 mg and the elimination of a second evening dose (which is associated with insomnia during Zyban? b.i.d. dosing), and; 3) improved compliance through once-a-day dosing. The aim of this clinical trial is to confirm single dose and steady state pharmacokinetic (PK) parameters of both bupropion and mecamylamine combined in this new formulation in order to inform the dose selection for the Proof of Concept Phase 2 clinical trial.,Study 1 is a randomized crossover bio-equivalence (pharmacokinetic rate and extent) comparison of the novel combination controlled-release product to the currently marketed sustained release bupropion tablet Zyban?). In Study 2, using similar methodology to Study 1, the effect of food upon PK parameters of the combination product will be assessed in a randomized, crossover design. In Study 3, the controlled-release capsule containing bupropion and mecamylamine will be clinically evaluated at steady state.